tbuckley/cabot-search huggingface dataset:
Ticagrelor–Aspirin Versus Clopidogrel–Aspirin Among <i>CYP2C19</i> Loss-of-Function Carriers With Minor Stroke or Transient Ischemic Attack in Relation to Renal Function: A Post Hoc Analysis of the CHANCE-2 Trial
Authors: Anxin Wang, Xuewei Xie, Xue Tian, S. Claiborne Johnston, Hao Li, Philip M. Bath, Yingting Zuo, Jing Jing, Jinxi Lin, Yilong Wang, Xingquan Zhao, Zixiao Li, Yong Jiang, Liping Liu, Xia Meng, Yongjun Wang
Journal: Annals of Internal Medicine (2022)

Evidence on the risk-benefit ratio of dual antiplatelet therapies among patients with stroke and impaired renal function is limited and inconsistent.To investigate the effect of renal function on the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin treatment.Post hoc analysis of a multicenter, randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04078737).202 centers in China.CYP2C19 loss-of-function allele carriers with minor stroke or transient ischemic attack.Ticagrelor-aspirin and clopidogrel-aspirin.Renal function was evaluated by estimated glomerular filtration rate (eGFR) levels. The primary efficacy and safety outcomes were recurrent stroke and severe or moderate bleeding within 90 days, respectively.Among 6378 patients, 4050 (63.5%) had normal (eGFR ≥90 mL/min/1.73 m2), 2010 (31.5%) had mildly decreased (eGFR 60 to 89 mL/min/1.73 m2), and 318 (5.0%) had moderately to severely decreased (eGFR <60 mL/min/1.73 m2) renal function. The corresponding differences in recurrent stroke between ticagrelor-aspirin and clopidogrel-aspirin for normal, mildly decreased, and moderately to severely decreased renal function was -2.8 percentage points (95% CI, -4.4 to -1.3 percentage points) (hazard ratio [HR], 0.63 [CI, 0.49 to 0.81]), -0.2 percentage point (CI, -2.4 to 2.0 percentage points) (HR, 0.98 [CI, 0.69 to 1.39]), and 3.7 percentage points (CI, -2.3 to 10.1 percentage points) (HR, 1.31 [CI, 0.48 to 3.55]), respectively. Rates of severe or moderate bleeding did not substantially differ by treatment assignments across eGFR categories.Renal function was only evaluated by using eGFR, and the proportion of patients with severely decreased renal function was low.Patients with normal, rather than impaired, renal function received greater benefit from ticagrelor-aspirin versus clopidogrel-aspirin.Ministry of Science and Technology of the People's Republic of China.
SARS-CoV-2 vaccination improves HBV seroconversion rate through heterological immunity
Authors: Moritz Anft, Krystallenia Paniskaki, Tina Giglio, Jacqueline Wellenkötter, Arturo Blazquez-Navarro, Toni L Meister, Toralf Roch, Claudia Giesecke-Thiel, Timm H Westhoff, Ulrik Stervbo, Stephanie Pfaender, Okan Cinkilic, Nina Babel
Journal: Kidney International (2022)
Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes
Authors: Kynon J. M. Benjamin, Qiang Chen, Andrew E. Jaffe, Joshua M. Stolz, Leonardo Collado-Torres, Louise A. Huuki-Myers, Emily E. Burke, Ria Arora, Arthur S. Feltrin, André Rocha Barbosa, Eugenia Radulescu, Giulio Pergola, Joo Heon Shin, William S. Ulrich, Amy Deep-Soboslay, Ran Tao, Mitsuyuki Matsumoto, Takeshi Saito, Katsunori Tajinda, Daniel J. Hoeppner, David A. Collier, Karim Malki, Bradley B. Miller, Maura Furey, Derrek Hibar, Hartmuth Kolb, Michael Didriksen, Lasse Folkersen, Tony Kam-Thong, Dheeraj Malhotra, Joo Heon Shin, Andrew E. Jaffe, Rujuta Narurkar, Richard E. Straub, Thomas M. Hyde, Joel E. Kleinman, Daniel R. Weinberger, Thomas M. Hyde, Joel E. Kleinman, Jennifer A. Erwin, Daniel R. Weinberger, Apuã C. M. Paquola
Journal: Nature Neuroscience (2022)
Health Care Access and Reproductive Rights
Authors: Linda Brubaker, Kirsten Bibbins-Domingo
Journal: JAMA (2022)

Heidi D. Nelson, MD, MPH; Blair G. Darney, PhD; Katherine Ahrens, PhD; Amanda Burgess, MPPM; Rebecca M. Jungbauer, DrPH; Amy Cantor, MD, MPH; Chandler Atchison, MPH; Karen B. Eden, PhD; Rose Goueth, PhD, MS; Rongwei Fu, PhD
Estimated Deaths Attributable to Excessive Alcohol Use Among US Adults Aged 20 to 64 Years, 2015 to 2019
Authors: Marissa B. Esser, Gregory Leung, Adam Sherk, Michele K. Bohm, Yong Liu, Hua Lu, Timothy S. Naimi
Journal: JAMA Network Open (2022)

Importance Alcohol consumption is a leading preventable cause of death in the US, and death rates from fully alcohol-attributable causes (eg, alcoholic liver disease) have increased in the past decade, including among adults aged 20 to 64 years. However, a comprehensive assessment of alcohol-attributable deaths among this population, including from partially alcohol-attributable causes, is lacking. Objective To estimate the mean annual number of deaths from excessive alcohol use relative to total deaths among adults aged 20 to 64 years overall; by sex, age group, and state; and as a proportion of total deaths. Design, Setting, and Participants This population-based cross-sectional study of mean annual alcohol-attributable deaths among US residents between January 1, 2015, and December 31, 2019, used population-attributable fractions. Data were analyzed from January 6, 2021, to May 2, 2022. Exposures Mean daily alcohol consumption among the 2 089 287 respondents to the 2015-2019 Behavioral Risk Factor Surveillance System was adjusted using national per capita alcohol sales to correct for underreporting. Adjusted mean daily alcohol consumption prevalence estimates were applied to relative risks to generate alcohol-attributable fractions for chronic partially alcohol-attributable conditions. Alcohol-attributable fractions based on blood alcohol concentrations were used to assess acute partially alcohol-attributable deaths. Main Outcomes and Measures Alcohol-attributable deaths for 58 causes of death, as defined in the Centers for Disease Control and Prevention’s Alcohol-Related Disease Impact application. Mortality data were from the National Vital Statistics System. Results During the 2015-2019 study period, of 694 660 mean deaths per year among adults aged 20 to 64 years (men: 432 575 [66.3%]; women: 262 085 [37.7%]), an estimated 12.9% (89 697 per year) were attributable to excessive alcohol consumption. This percentage was higher among men (15.0%) than women (9.4%). By state, alcohol-attributable deaths ranged from 9.3% of total deaths in Mississippi to 21.7% in New Mexico. Among adults aged 20 to 49 years, alcohol-attributable deaths (44 981 mean annual deaths) accounted for an estimated 20.3% of total deaths. Conclusions And Relevance The findings of this cross-sectional study suggest that an estimated 1 in 8 total deaths among US adults aged 20 to 64 years were attributable to excessive alcohol use, including 1 in 5 deaths among adults aged 20 to 49 years. The number of premature deaths could be reduced with increased implementation of evidenced-based, population-level alcohol policies, such as increasing alcohol taxes or regulating alcohol outlet density.
C-CAT: The National Datacenter for Cancer Genomic Medicine in Japan
Authors: Takashi Kohno, Mamoru Kato, Shinji Kohsaka, Tomohisa Sudo, Ikuo Tamai, Yuichi Shiraishi, Yusuke Okuma, Daisuke Ogasawara, Tatsuya Suzuki, Teruhiko Yoshida, Hiroyuki Mano
Journal: Cancer Discovery (2022)

Since June 2019, under the umbrella of the national health insurance system, Japan has started cancer genomic medicine (CGM) with comprehensive genomic profiling (CGP) tests. The Ministry of Health, Labour and Welfare (MHLW) of Japan constructed a network of CGM hospitals (a total of 233 institutes as of July 1, 2022) and established the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national datacenter for CGM. Clinical information and genomic data from the CGP tests are securely transferred to C-CAT, which then generates "C-CAT Findings" reports containing information of clinical annotation and matched clinical trials based on the CGP data. As of June 30, 2022, a total of 36,340 datapoints of clinical/genomic information are aggregated in C-CAT, and the number is expected to increase swiftly. The data are now open for sharing with not only the CGM hospitals but also other academic institutions and industries.
Next generation of neurological therapeutics: Native and bioengineered extracellular vesicles derived from stem cells
Authors: Shilin Jin, Zhongyue Lv, Lin Kang, Jiayi Wang, Chengcheng Tan, Liming Shen, Liang Wang, Jing Liu
Journal: Asian Journal of Pharmaceutical Sciences (2022)

Extracellular vesicles (EVs)-based cell-free therapy, particularly stem cell-derived extracellular vesicles (SC-EVs), offers new insights into treating a series of neurological disorders and becomes a promising candidate for alternative stem cell regenerative therapy. Currently, SC-EVs are considered direct therapeutic agents by themselves and/or dynamic delivery systems as they have a similar regenerative capacity of stem cells to promote neurogenesis and can easily load many functional small molecules to recipient cells in the central nervous system. Meanwhile, as non-living entities, SC-EVs avoid the uncontrollability and manufacturability limitations of live stem cell products in vivo (e.g., low survival rate, immune response, and tumorigenicity) and in vitro (e.g., restricted sources, complex preparation processes, poor quality control, low storage, shipping instability, and ethical controversy) by strict quality control system. Moreover, SC-EVs can be engineered or designed to enhance further overall yield, increase bioactivity, improve targeting, and extend their half-life. Here, this review provides an overview on the biological properties of SC-EVs, and the current progress in the strategies of native or bioengineered SC-EVs for nerve injury repairing is presented. Then we further summarize the challenges of recent research and perspectives for successful clinical application to advance SC-EVs from bench to bedside in neurological diseases.
The Heat Is On: 20-HETE Instructs an Immunosuppressive Phenotype in Cancer-Associated Fibroblasts
Authors: Jo A. Van Ginderachter
Journal: Cancer Research (2022)

Immunotherapy of cancer is a burgeoning field of research since the realization that our immune system intrinsically has the capacity to restrict tumor occurrence and progression. Though strategies to maximize antitumor T-cell activation are well established, the efficacy of these therapies is limited by an insufficient knowledge of the intricate tumor microenvironment and its capacity to thwart antitumor immunity. Chen and colleagues now uncover a novel immunosuppressive pathway in non-small cell lung carcinoma. Overexpression of cytochrome P450F2 in cancer cells increases production of 20-hydroxyeicosatetraenoic acid, which instructs the expression of immunosuppressive molecules in cancer-associated fibroblasts by binding the GPR75 receptor and activating STAT3/c-Jun signaling. This work proposes several innovative therapeutic anchor points that may improve the efficacy of existing immunotherapies. See related article by Chen et al., p. 4016.
Accidentals of the DNA Symphony
Authors: Anjui Wu, Gerhardt Attard
Journal: Cancer Research (2022)

Abstract Cancer epigenome profiling such as DNA methylation (5mC) and DNA hydroxymethylation (5hmC) is emerging as a sensitive approach for cancer detection and risk stratification. 5mC modification has been widely described in many cancer types including prostate cancer; however, the 5hmC landscape is yet to be explored. In this issue of Cancer Research, Sjöström and colleagues have comprehensively incorporated genomic, transcriptomic, and epigenomic, including 5hmC, data to interrogate the molecular evolution of prostate cancer. See related article by Sjöström et al., p. 3888
Highlights from Recent Cancer Literature
Journal: Cancer Research (2022)

Rapa Blocking Side EffectsThe mammalian/mechanistic target of rapamycin kinase (mTOR) is a core regulator of cell growth, metabolism, and translation, and is commonly dysregulated in brain tumors.Several mTOR inhibitors have been identified, but the multifarious functions of this signaling pathway mean that such inhibitors have substantial side effects.Here, a combinatorial approach was devised to limit the activity of a brainpermeant mTOR inhibitor, RapaLink-1, in tissues outside the brain.Zhang and colleagues found that RapaLink-1 requires the FKBP12 protein for its inhibitory effect in cells and generated brain-impermeant derivatives of a natural ligand of FKBP12, FK506, with the goal of blocking this activity.One derivative, RapaBlock, potently limited RapaLink activity but was brain impermeant; thus, the administration of both compounds allowed mTOR inhibition in the brain while sparing other tissues.Finally, the authors demonstrated that the strategy used in this case may be more broadly applicable to other kinase inhibitors via their chemical coupling to FK506 fragments.
Lung CAFs Show T Cells the Velvet Rope
Authors: Mara H. Sherman
Journal: Cancer Discovery (2022)

Summary: Cancer-associated fibroblasts share defined features with fibroblasts in secondary lymphoid organs, including the ability to regulate immune cell localization. In this issue of Cancer Discovery, Grout and colleagues perform multimodal analysis of human lung cancer specimens and identify two distinct fibroblast populations associated with spatial exclusion of T cells from tumor cell nests. See related article by Grout et al., p. 2606 (3).
Challenges and Emerging Opportunities for Targeting mTOR in Cancer
Authors: Kris C. Wood, J. Silvio Gutkind
Journal: Cancer Research (2022)

Abstract The mechanistic target of rapamycin (mTOR) plays a key role in normal and malignant cell growth. However, pharmacologic targeting of mTOR in cancer has shown little clinical benefit, in spite of aberrant hyperactivation of mTOR in most solid tumors. Here, we discuss possible reasons for the reduced clinical efficacy of mTOR inhibition and highlight lessons learned from recent combination clinical trials and approved indications of mTOR inhibitors in cancer. We also discuss how the emerging systems level understanding of mTOR signaling in cancer can be exploited for the clinical development of novel multimodal precision targeted therapies and immunotherapies aimed at achieving tumor remission.
Targeting the tumor stroma for cancer therapy
Authors: Maosen Xu, Tao Zhang, Ruolan Xia, Yuquan Wei, Xiawei Wei
Journal: Molecular Cancer (2022)

Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part of the tumor microenvironment, the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer-associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance. Over the past few decades, numerous studies have been conducted to study the interaction and crosstalk between stromal components and neoplastic cells. Meanwhile, we have also witnessed an exponential increase in the investigation and recognition of the critical roles of tumor stroma in solid tumors. A series of clinical trials targeting the tumor stroma have been launched continually. In this review, we introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers. We also elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside.
Arginase-2-specific cytotoxic T cells specifically recognize functional regulatory T cells
Authors: Stine Emilie Weis-Banke, Thomas Landkildehus Lisle, Maria Perez-Penco, Aimilia Schina, Mie Linder Hübbe, Majken Siersbæk, Morten Orebo Holmström, Mia Aaboe Jørgensen, Inge Marie Svane, Özcan Met, Niels Ødum, Daniel Hargbøl Madsen, Marco Donia, Lars Grøntved, Mads Hald Andersen
Journal: Journal for ImmunoTherapy of Cancer (2022)

High expression of the metabolic enzyme arginase-2 (ARG2) by cancer cells, regulatory immune cells, or cells of the tumor stroma can reduce the availability of arginine (L-Arg) in the tumor microenvironment (TME). Depletion of L-Arg has detrimental consequences for T cells and leads to T-cell dysfunction and suppression of anticancer immune responses. Previous work from our group has demonstrated the presence of proinflammatory ARG2-specific CD4 T cells that inhibited tumor growth in murine models on activation with ARG2-derived peptides. In this study, we investigated the natural occurrence of ARG2-specific CD8 T cells in both healthy donors (HDs) and patients with cancer, along with their immunomodulatory capabilities in the context of the TME. A library of 15 major histocompatibility complex (MHC) class I-restricted ARG2-derived peptides were screened in HD peripheral blood mononuclear cells using interferon gamma (IFN-γ) ELISPOT. ARG2-specific CD8 T-cell responses were identified using intracellular cytokine staining and ARG2-specific CD8 T-cell cultures were established by enrichment and rapid expansion following in vitro peptide stimulation. The reactivity of the cultures toward ARG2-expressing cells, including cancer cell lines and activated regulatory T cells (Tregs), was assessed using IFN-γ ELISPOT and a chromium release assay. The Treg signature was validated based on proliferation suppression assays, flow cytometry and quantitative reverse transcription PCR (RT-qPCR). In addition, vaccinations with ARG2-derived epitopes were performed in the murine Pan02 tumor model, and induction of ARG2-specific T-cell responses was evaluated with IFN-γ ELISPOT. RNAseq and subsequent GO-term and ImmuCC analysis was performed on the tumor tissue. We describe the existence of ARG2-specific CD8+ T cells and demonstrate these CD8+ T-cell responses in both HDs and patients with cancer. ARG2-specific T cells recognize and react to an ARG2-derived peptide presented in the context of HLA-B8 and exert their cytotoxic function against cancer cells with endogenous ARG2 expression. We demonstrate that ARG2-specific T cells can specifically recognize and react to activated Tregs with high ARG2 expression. Finally, we observe tumor growth suppression and antitumorigenic immunomodulation following ARG2 vaccination in an in vivo setting. These findings highlight the ability of ARG2-specific T cells to modulate the immunosuppressive TME and suggest that ARG2-based immunomodulatory vaccines may be an interesting option for cancer immunotherapy.
Correction: Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial
Authors: Qian Jiang, Zongru Li, Yazhen Qin, Weiming Li, Na Xu, Bingcheng Liu, Yanli Zhang, Li Meng, Huanling Zhu, Xin Du, Suning Chen, Yang Liang, Yu Hu, Xiaoli Liu, Yongping Song, Lichuang Men, Zi Chen, Qian Niu, Hengbang Wang, Ming Lu, Dajun Yang, Yifan Zhai, Xiaojun Huang
Journal: Journal of Hematology & Oncology (2022)
Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies
Authors: Hu Fang, Helen H. N. Yan, Rebecca A. Bilardi, Christoffer Flensburg, Haocheng Yang, Jayne A. Barbour, Hoi Cheong Siu, Michelle Turski, Edward Chew, Zhen Xu, Siu T. Lam, Rakesh Sharma, Mengya Xu, Junshi Li, Ho W. Ip, Carol Y. M. Cheung, Michael S. Y. Huen, E. Alejandro Sweet-Cordero, Ian J. Majewski, Suet Y. Leung, Jason W. H. Wong
Journal: Genome Medicine (2022)

Abstract Background Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. Methods This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCV sig ) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. Results Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCV sig . A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCV sig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCV sig in cell lines and organoids. Conclusions In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.
Common features of neurodegenerative disease: exploring the brain-eye connection and beyond (part 2): the 2021 pre-symposium of the 15th international conference on Alzheimer’s and Parkinson’s diseases
Authors: Sharyn L. Rossi, Preeti Subramanian, Guojun Bu, Adriana Di Polo, Todd E. Golde, Diane E. Bovenkamp
Journal: Molecular Neurodegeneration (2022)

BrightFocus Foundation sponsored the third iteration of the "Common Features of Neurodegenerative Disease: Exploring the Brain-Eye Connection and Beyond" preconference symposium that preceded the 15th International Conference on Alzheimer's and Parkinson's Diseases (AD/PD 2021).Part 1 of the meeting report was previously published in Molecular Neurodegeneration.This completes the description of the meeting with Part 2. Session III, "Why are the vascular components and blood-brain/blood-retina barriers of the brain and eye important contributors to the tipping point between health and disease?" was chaired by Dr. Adriana Di Polo.Both the brain and the eye are highly vascularized organs that contain a dense capillary network.The neurovascular unit (NVU) is a community of cells including neurons, astrocytes, endothelial cells, pericytes, and